This invention refers to a process for the preparation of a pharmaceutically active chemical combination constituted by the association, through chemical bonds, of two units equal to one another, having pharmacological activity.
The invention also relates to said pharmacologically active chemical combination obtained through said process, and its utilization for the preparation of pharmaceutical compositions having pharmacological activity.
The invention furtherly relates to pharmaceutical compositions comprising said chemical combination as active principle.
The researchers of the whole world have been engaged for many years in the study and development of pharmacologically active compounds, in order to obtain new drugs. Parallelly to this line of research, great importance is given also the research aiming at finding systems allowing to improve the therapeutical performances of large consumption drugs that are already marketed. Many medicines known and commonly utilized in therapy, while being provided with a good pharmacological activity, have often some drawbacks; some of these problems are due, for instance, to the fact that, often because of unsuitable hydrophilic or hydrophobic, characteristics, the drug may have a far from optimum bioavailability, which may constitute an obstacle to reach the action site, with ensuing reduction in the therapeutical activity. Furthermore, once the molecule constituting the active principle has entered the circle, it may be subjected to the activity of aspecific enzymes, which may cause adverse reactions of different nature; furthermore, the administration system of the drug may sometimes involve problems, due for instance to the chemical-physical instability of the molecule that constitute the active principle, with ensuing inactivation risks and also marked inconveniences for the patient.
As known, the systems suitable to improve the tharapeutical performances of drugs require, for instance, the use of appropriate delivery systems, based on appropriate pharmaceutical formulations which, while keeping the activity of the drug inalterated, improve its absorption, the bioavalability and make its administration easier. Other systems used for this purpose involve the preparation of prodrugs, precursor compounds, mostly pharmacologically inert, of the real drug, which are transformed into the pharmacologically active product through one or more chemical and/or enzymatic reactions. Different examples in this sense are reported in the literature, some of which have had a remarkable success from both therapeutical and commercial points of view.
A particular interpretation of the xe2x80x9cprodrugxe2x80x9d concept is represented, as is reported in the literature by some known products used in the inflammatory pathologies of the intestine, such as for ice Olsalazine and Sulfasalazine, whose molecular structure is derived from two phamacologically active units, either equal to or different from one another, directly bound to one another by transformation of the aninic groups of the two molecules in to an azoic type bond. Generally, the aforementioned therapeutical approaches have the drawback of supplying often non constant and non foreseeable responses during the therapy being carried on, with ensuing difficulty in the choice of the adequate therapy and possible inconveniences for the patients subjected to such therapies.
A very much felt problem in the field of pharmacological therapy is that associated to the duration of the effect reached through the administration of the drug. Usually, in fact, once administered, the drug employs a variable time, which depends on the whole of all the factors already considered (for instance, bioavailability, absorption level, stability, administration method) to reach the target; once the target has been reached, the drug exerts its activity, whose effect generally depends on the administered dose, after which it undergoes several chemical-physical changes, and is metabolized and eliminated in variable times. Because of this mechanism of activity, most drugs cannot achieve a long-lasting effect; in most cases; such effect disappears as soon as die metabolization process starts. This causes considerable inconveniences since, to obtain a longer effect, it is almost always necessary to administer drug doses at shorter intervals, with a risk of accumulation and ensuing increase in side effects.
Object of this invention is therefore to realize a process for the preparation of a pharmacologically active chemical combination allowing the controlled release of the constituent active principles once the target site has been reached.
A further object of this invention is to realize a process for the realization of a pharmacologically active chemical combination with good characteristics of bioavailability, well tolerated (often even more than he individual constituent active principle) and of easy administration
Still a further object of this invention is to realize a process for the preparation of a pharmacologically active chemical combination allowing to obtain a long-lasting therapeutical effect, without recourse to a proportional increase in the frequency of the doses used.
Still another object of this invention is to provide a pharmacologically active chemical combination, realized by means of said process, as well as pharmaceutical compositions comprising as active principle said chemical combination.
These and still other objects and related advantages, which will be more clearly apparent from the following description, are reached by a process for the preparation of a pharmacologically active chemical combination, which, according to this invention, consists in chemically combining a first and a second unit (or radical) of molecular structures corresponding to pharmacologically active compounds, through a system having a xe2x80x9cbidentatexe2x80x9d structure, so as to realize a chemical combination having the following general formula:
Mxe2x80x94Axe2x80x94Xxe2x80x94Bxe2x80x94Mxe2x80x83xe2x80x83(I)
where
M indicates said first and second units (or radicals) of molecular structures corresponding to pharmacologically active compounds, said units (or radicals) being related down to said molecular structures by saturation of the free valences with atoms or groups of atoms such as hydrogen, OH group, OEt group;
X indicates a xe2x80x9cbidentatexe2x80x9d structure, suitable to interconnect said M according to the general formula (I);
A and B are equal to or different from one another and indicate functional groups which allow said interconnection between said M and said X.
More particularly, always according to this invention, said M, equal to one another, are chosen among the following groups: 
According to this invention, said X having a xe2x80x9cbidentatexe2x80x9d molecular structure, suitable to interconnect said M according to the general formula (I) is chosen among:
saturated, unsaturated, linear, branched or cyclic, substituted or unsubstituted alkyl chain;
substituded or unsubstituted arylidenic benzenoid, naphthalenic, heteroaromatic pyridinic, pyrimidinic, pyrazolic, pyrazinic, imidazolic, benzimidazolic system;
arylaliphatic system in which the first of said functional groups A and B is on the aromatic portion and the second of said functional groups A and B is on the aliphatic portion, said aromatic portion being constituted by a substituted or unsubstituted benzenoid or heteroaromatic system and said aliphatic portion being constituted by a saturated or unsaturated, linear or branched, substituted or unsubstituted alkylidenic group;
xe2x80x83xe2x80x94(CH2)mxe2x80x94Zxe2x80x94(CH2)nxe2x80x94xe2x80x83xe2x80x83(CXLI)
xe2x80x83where
m,n=1-3, with m=n or mxe2x89xa0n
Z=O, substituted or unsubstituted benzenoidic or heteroaromatic ring 
X=O,S
Y(CH2CH2)2xe2x80x83xe2x80x83(XCVI)
Y=S, Sxe2x80x94S, (OCH2CH2O)nn=1-5,
Rxe2x80x94N where R is chosen among: substituted or unsubstituted, linear, branched alkyl, substituted or unsubstituted aryl 
Said functional groups indicated by A and B which allow said interconnection between said M and said X are chosen, always according to this invention, among: xe2x80x94O, S, Nxe2x80x94R, Cxe2x95x90Nxe2x80x94R, CO, C(xe2x95x90Nxe2x80x94R)xe2x80x94NH, where R is chosen among hydrogen, cyclic, branched, linear alkyl group.
Particularly, when the M unit is chosen as (XLIV), the free valence is saturated with the hydrogen atom; when the M unit is chosen as (CX), (CXII), (CV) the free valence is saturated with the OEt group; in all the other cases the free valence is saturated with the OH group. Still, when said M is chosen as (XLIV), said functional groups A and B are chosen among CO, C(xe2x95x90Nxe2x80x94R)xe2x80x94NH, Cxe2x95x90Nxe2x80x94R, while in all the other cases A and B are chosen among O, S, Nxe2x80x94R.
In fact, it has been observed that the pharmacologically active chemical combination of the general formula (I) does not constitute the active principle as such, but undergoes a conversion in the bioactive units corresponding to M; such conversion takes place in different ways and times, according to the treatment conditions, the target or activity site, the administration doses and the pathology ascertained. Therefore, this allows the controlled release of the constituent active principles, and particularly the controlled release of the molecular structures corresponding to M which derive from compounds having a pharmacological activity; such release may happen gradually, for instance when the product corresponding to said chemical combination, obtained according to how M, A, B and X are chosen among the aforementioned ones, has reached the so-called target or active site, allowing in this way to obtain a pharmacological effect which is not only significant, thanks to the release of effective concentrations of active principle, but also long lasting, thanks to the slow release near the action site. In this way, a marked improvement is observed which concerns not only the therapeutical performance but also the toxicological aspects, with ensuing reduction, in many cases, of general and local toxicity.
Besides, the chemical combination represented through the general formula (I) allows in many cases and according to how A and B are chosen to xe2x80x9cmaskxe2x80x9d some functional groups or part of them possibly present on said radicals indicated by M, said functional groups, or part of them, being sometimes responsible for induced adverse reactions that are noticed during the treatment with some drugs whose molecular structure is characterized by the presence of said functional groups. For instance, as is known, the carboxylic function, which is present in the molecular structure of the known non steroidal anti-inflammatory drugs, results to be determinant to direct the molecule towards the inflammatory focus, but also largely responsible for the induced adverse reactions on the gastro-intestinal apparatus. In the case of products of the general formula (I) where M is chosen, for instance, among the units described in group 15, as such function is masked, an improved bioavailability, an improved toxicological profile and a good therapeutical effectiveness are observed.
In particular, a clearly improved gastrointestinal tolerability is obtained relatively to the known anti-inflammatory drugs, while keeping an unchanged effectiveness and demonstrating therefore a reduced gastro-harmfulness. The protracted and controlled release characteristic of the chemical combination according to this invention involves, as said above, also important cynetic advantages, and allows to use said combination in chronic pathologies requiring pharmacological treatments protracted in the time, without incurring the side effects that affect the kidneys and the liver, caused by massive pharmacological treatments protracted in the time.
Always according to this invention, the chemical combination of general formula, (I) has chemical-physical and biochemical characteristics such as to ensure in most cases a good oral absorption and a protracted permanence in the circle, with ensuing considerable advantages, not only therapeutical, but also of administration Always according to this invention, when said X structure suitable to interconnect, through said A and B, said M units, is chosen equal to
Y(CH2CH2)2xe2x80x83xe2x80x83(XCVI)
where Y is equal to (OCH2CH2O)2 
said structure, depending on the conditions and once the release of M units has taken place according to the above description, can exert a high anti-ischemic activity, thanks to the remarkable vasoactive properties that characterize some aliphatic glycols from which said X has been derived; said anti-ischemic activity, accompanied by a very low toxicity, has to be considered, depending on how M, A and B are chosen, as additional and complementary to the main pharmacological activity for which the combination is used, with ensuing increase of the global pharmacological effect, without any increase in the administered doses.
Besides, when said X is chosen equal to xe2x80x94(CH2)7xe2x80x94, said A and B are chosen equal to CO, the fragment corresponds to the azelaic acid and has itself antibacterial and anti-inflammatory properties and may be advantageously used; in the interconnection of suitable M units, so as to develop a synergical effect.
Always according to this invention, said X, such as for instance a benzenoid arylidenic system, when associated to suitable A and B chosen equal to O, gives rise to fragments corresponding to products having anti-oxidant properties, such as, for instance: 
(residue deriving from the structure of hydroquinone), or having anti-inflammatory properties when X is chosen equal to (CXLVIII), such as, for instance: 
(residue deriving from the structure of olsalazine).
Always according to this invention, the products deriving from said pharmacologically active chemical combination of the general formula (I) are also obtainable as pharmacologically acceptable salts according to techniques of known type, in order to improve the characteristics of solubility, chemical-physical and biochemical stability and the administration modalities.
Particularly advantageous, according to this invention, proved to be the preparations of the chemical combination of the general formula (I), realized as described in the following examples, given by way of non limitative indication of the protection scope of the invention.